PNNL

Abstract

Pharmacokinetics of dichloroacetate (DCA) in naive and glutathione-S-transferase-zeta (GSTzeta) depleted rats was studied at doses approaching human daily exposure levels. In vitro metabolism of DCA by rat and human liver cytosol was also compared. Jugular vein cannulated male Fischer-344 rats were administered (i.v or gavage) with graded doses of DCA ranging from 0.05-20 mg/kg and time-course blood samples collected from the cannula. GSTzeta was depleted by exposing rats to DCA (0.2 g/L DCA) in drinking water for 7 days. Elimination of DCA by naive rats was so rapid that only the 1-20 mg/kg i.v. and 5 and 20 mg/kg gavage doses provided plasma concentrations above the method detection limit. GSTzeta depletion slowed DCA elimination from plasma allowing kinetic analysis of doses as low as 0.05 mg/kg. DCA elimination was strongly dose-dependent in the naive rats with total body clearance declining with increasing dose. In the GSTzeta depleted rats, the pharmacokinetics became linear at doses #1 mg/kg. All oral doses were rapidly absorbed without any lag time. At higher oral doses (?5 mg/kg in GSTzeta depleted and ?20 mg/kg in naive), secondary peaks in the plasma concentration appeared long after the completion of the initial absorption phase. Virtually all the dose was eliminated through metabolic clearance; the rate of urinary elimination of DCA was 0.3), which supported the use of GSTzeta depleted rats as a model for assessing kinetics of DCA in humans. Oral bioavailability of DCA was 0-13% in naive and 14-75% in GSTzeta depleted rats. Oral bioavailability of DCA to humans through consumption of drinking water was predicted to be a maximum of 0.05%.